title: Genomic insights into triple-negative and HER2-positive breast cancers using isogenic model systems.
abstract: BACKGROUND
  In general, genomic signatures of breast cancer subtypes have little or no overlap owing to the heterogeneous genetic backgrounds of study samples. Thus, obtaining a reliable signature in the context of isogenic nature of the cells has been challenging and the precise contribution of isogenic triple negative breast cancer (TNBC) versus non-TNBC remains poorly defined.
  
  
  METHODS
  We established isogenic stable cell lines representing TNBC and Human Epidermal Growth Factor Receptor 2 positive (HER2+) breast cancers by introducing HER2 in TNBC cell lines MDA-MB-231 and MDA-MB-468. We examined protein level expression and functionality of the transfected receptor by treatment with an antagonist of HER2. Using microarray profiling, we obtained a comprehensive gene list of differentially expressed between TNBC and HER2+ clones. We identified and validated underlying isogenic components using qPCR and also compared results with expression data from patients with similar breast cancer subtypes.
  
  
  RESULTS
  We identified 544 and 1087 statistically significant differentially expressed genes between isogenic TNBC and HER2+ samples in MDA-MB-231 and MDA-MB-468 backgrounds respectively and a shared signature of 49 genes. By comparing results from MDA-MB-231 and MDA-MB-468 backgrounds with two patient microarray datasets, we identified 17 and 22 common genes with same expression trend respectively. Additionally, we identified 56 and 78 genes from MDA-MB-231 and MDA-MB-468 comparisons respectively present in our published RNA-seq data.
  
  
  CONCLUSIONS
  Using our unique model system, we have identified an isogenic gene expression signature between TNBC and HER2+ breast cancer. A portion of our results was also verified in patient data samples, indicating an existence of isogenic element associated with HER2 status between genetically heterogeneous breast cancer samples. These findings may potentially contribute to the development of molecular platform that would be valuable for diagnostic and therapeutic decision for TNBC and in distinguishing it from HER2+ subtype.
authors.affiliation: McCormick Genomic and Proteomics Center, School of Medicine and Health Sciences, the George Washington University, Washington, District of Columbia, United States of America ; Department of Biochemistry and Molecular Medicine, School of Medicine and Health Sciences, the George Washington University, Washington, District of Columbia, United States of America.
authors.forename: Prakriti
authors.initials: P
authors.lastname: Mudvari
authors.forename: Kazufumi
authors.initials: K
authors.lastname: Ohshiro
authors.forename: Vasudha
authors.initials: V
authors.lastname: Nair
authors.forename: Anelia
authors.initials: A
authors.lastname: Horvath
authors.forename: Rakesh
authors.initials: R
authors.lastname: Kumar
mesh_terms: D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D023281:Genomics; D006801:Humans; D008954:Models, Biological; D020411:Oligonucleotide Array Sequence Analysis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D015203:Reproducibility of Results; D064726:Triple Negative Breast Neoplasms / Q000235:genetics* / Q000378:metabolism*
chemical_list: D018719:Erb-b2 Receptor Tyrosine Kinases; C508053:ERBB2 protein, human